Urotensin II: a new player in vascular and myocardial disease?

There has been considerable excitement and a flurry of contemporary research into the physiological actions of the 11-amino-acid peptide, urotensin II ; however, urotensin II itself is not a new discovery. It was first described approximately 35 years ago in the urophysis of the teleost fish [1]. It was, in fact, the discovery by Ames et al. [2]. of an endogenous ligand for urotensin II (GPR 14) that has stimulated this recent research activity. In many ways urotensin II mimics the actions of other key neurohormonal factors in driving a variety of cardiac and vascular disease processes [3]. These include vasoconstriction (in some, but not all, vascular beds), as well as mitogenic, trophic and pro-fibrotic effects. However, key differences can be observed between urotensin II and other well-characterized systems, such as the renin– angiotensin–aldosterone system (RAAS) and the endothelin system. In particular, the vasoconstrictor effect of urotensin II is either weak or absent in a variety of human vascular beds [4,5]. Moreover, it may actually act as a vasodilator in certain beds, such as in the pulmonary vasculature [6] (via activation of nitric oxide, vasodilator prostaglandins and perhaps endothelium-derived hyperpolarizing factor). Furthermore, clear-cut data regarding the effect of exogenous arterial infusion of urotensin II on vascular tone in the human forearm vascular bed are lacking [7,8]. Thus, the precise role of urotensin II in modulating vascular tone in the resting state in man remains somewhat uncertain. Even less clear is the role of urotensin II in cardiovascular disease states. Within the myocardium, there is evidence of activation of both urotensin II and its receptor in the post-myocardial infarction [9] and established chronic heart failure setting [10]. This activation may be of considerable pathophysiological significance, given the aforementioned hypertrophic and pro-fibrogenic effects [9] of activation of this system. In addition, little is known about the role of urotensin II in the peripheral vasculature in disease states. The observations in this issue of Clinical Science by Totsune and colleagues [11] regarding the presence of urotensin II precursor mRNA, as well as that of the urotensin II receptor within endothelial cells, may be of importance in this regard. In particular, they suggest that urotensin II activity may be altered by and perhaps contribute to vascular diseases associated with endothelial dysfunction. Plasma levels of circulating peptides are generally extremely insensitive measures of their systemic activation, and may also poorly reflect local activity. Nevertheless, they can provide insight into pathophysiological associations of bioactive peptides with various disease states. For example, endothelin-1 is released primarily by peripheral vascular endothelial cells, with most of that release being in an abluminal direction, i.e. directed towards the vascular smooth muscle cell [12]. Approx. 20 % of released endothelin-1 is directed towards the vessel lumen. Thus, elevated plasma levels denote a substantially activated endothelin system. In contrast, the source of urotensin II in man is largely unknown, both in normal subjects and in disease states. Indeed, plasma levels may reflect release from a number of potential sources, including the kidney, central nervous system and adrenal gland [6], as well as from peripheral vascular endothelial cells. Peptide plasma levels are the net result of both endogenous production and clearance. Clearance pathways for urotensin II are unknown. Some insight into urotensin II clearance via the kidney has been gleaned from the observation that urotensin II levels are roughly 2-fold higher in patients with renal dysfunction [13]. However, the authors of that study were unable to ascertain whether this was entirely due to reduced renal clearance or whether there was a contribution via the activation of urotensin II production. Similarly, patients with chronic heart failure have been shown to have elevated levels in some, but not all, studies [14–16]. Again, the relative contribution of impaired renal clearance to elevation of urotensin II peptide in this setting cannot be clearly determined based on available data. Because diabetes mellitus is associated with accelerated vascular disease, as well as direct effects on the myocardium, the relationship of vasoconstrictor systems to this disease are of great interest. This interest is enhanced with respect to urotensin II because of the observation that there is increased expression of urotensin II in atherosclerotic lesions, specifically within infiltrating macrophages [17]. Vascular complications are in fact the major cause of morbidity and early mortality in diabetic patients. In addition to glucose-dependent pathways, such as hyperglycaemia and the formation of advanced glycation end-products, glucose-independent mechanisms are also major contributors to diabetic vasculopathy. The latter not only include the effects of hypertension and dyslipidaemia, but also the dysregulation of vasoactive hormone systems. The RAAS has been the most extensively studied system in diabetes, where, despite suppression of systemic RAAS activity, therapeutic blockade with both angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers provide vascular protection. This apparent paradox has been explained by independent